Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS:We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (n=42) or emricasan (25 mg, n=44), twice daily for 3 months; subjects then received open-label emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS:Seventy-four patients completed the 3-month study period (40 given emricasan and 34 given placebo); 69 patients received open-label emricasan for 3 months afterward. At the 3-month timepoint, emricasan significantly reduced mean MELD (P=.003) and Child-Pugh (P=.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between emricasan and placebo groups in mean MELD (P=.466) or Child-Pugh (P=.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P=.02) and caspase 3/7 (P<.001), but not cleaved CK-18 (P=.092), decreased significantly at 3 months in the emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS:In a randomized trial of patients with cirrhosis, we found 3 months treatment with emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT002209456.

BACKGROUND:Limited data exist with regard to treatment outcomes in Asian Americans with chronic hepatitis C (CHC). We evaluated sofosbuvir (SOF)-based regimens in a national cohort of Asian Americans. METHODS:Eligible Asian Americans patients with CHC who had posttreatment follow-up of 24 weeks for SOF -based therapies from December 2013 to June 2017 were enrolled from 11 sites across the United States. The primary endpoint was sustained virologic response (SVR) rates at posttreatment weeks 12 and 24. Secondary endpoints were to evaluate safety by tolerability and adverse events (AEs). RESULTS:Among 231 patients screened, 186 were enrolled. At baseline, 31% (57/186) patients were cirrhotic, 34% (63/186) were treatment experienced. Most of the subjects (42%, 79/186) received ledispavir/SOF therapy. The overall SVR12 was 95%, ranging from 86% in genotype (GT) 1b on SOF+ribavirin to 100% in GT 1b patients on ledipasvir/SOF at subgroup analyses. SVR12 was significantly lower in cirrhotic than in noncirrhotic patients [88% (50/57) vs. 98% (126/129), P<0.01]. Stratified by GT, SVR12 were: 96% (43/45) in GT 1a; 93% (67/72) in GT 1b; 100% (23/23) in GT 2; 90% (19/21) in GT 3; 100% (1/1) in GT 4; 83% (5/6) in GT 5; and 100% (16/16) in GT 6. Cirrhotic patients with treatment failure were primarily GT 1, (GT 1a, n=2; GT 1b, n=4) with 1 GT 5 (n=1). Patients tolerated the treatment without serious AEs. Late relapse occurred in 1 patient after achieving SVR12. CONCLUSIONS:In Asian Americans with CHC, SOF-based regimens were well tolerated without serious AEs and could achieve high SVR12 regardless of hepatitis C viral infection GT.

To receive CME/MOC credit for this activity, please go to: http://acgjournalcme.gi.org/Article Title: Refractory Ascites in Liver Cirrhosis.

Treatment of chronic hepatitis C virus (HCV) infection has been revolutionized with the development of direct-acting antiviral agents (DAAs). Eight to twelve weeks of all-oral, once-daily treatments is now the standard of care and viral eradication can be achieved in >95% across different patient populations. Despite these advances, several unresolved issues remain, including treatment of HCV genotype 3, chronic kidney disease, and in patients in whom DAA therapy has failed. Glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, GLE/PIB and SOF/VEL/VOX are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Here, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.

BACKGROUND & AIMS/OBJECTIVE:We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET). METHODS:We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS:The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12. CONCLUSIONS:In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Chronic hepatitis B virus (HBV) remains a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Because chronic hepatitis B infection is rarely eradicated, preventing mother-to-child transmission (MTCT) is the most effective strategy to eliminate HBV globally. Although immunoprophylaxis strategy is widely available and effective for infants born to mothers with chronic hepatitis B infection, postnatal immunoprophylaxis fails in approximately 5-10 % of infants, and this failure rate goes up to 30 % in infants born to highly viremic mothers. Mothers with HBV DNA levels above 200,000 IU/mL should be managed aggressively with antiviral therapy because viral load is the strongest independent risk factor for immunoprophylaxis failure. Emerging data suggest that initiation of antiviral therapy in late pregnancy in highly viremic mothers can prevent immunoprophylaxis failure in their infants. Reducing viral load to target levels below 200,000 IU/mL at delivery is a practical approach to control MTCT. This review focuses on viral factors in mothers associated with MTCT.

Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI. Electronic medical records were reviewed for patient medication list, history of herbal medicine or supplement use, and pre-biopsy liver function test (LFT) results. Clinical and pathologic correlation was used to determine the causative or related agents for DILI. We then assessed histopathologic features of liver injury and categorized biopsy findings as primarily bile duct injury, lobular/portal hepatitis, or mixed changes. 604 total liver biopsies for hepatitis or liver injury were identified, of which 70 cases (11.6%) carried the diagnosis of DILI confirmed by clinical correlation. The most common etiologies associated with DILI were supplements and herbal products (31.4%), antimicrobials (14.3%), chemotherapeutics (11.4%), antilipidemics (7.1%) and immunomodulatory agents (7.1%). LFT results positively correlated with histological findings. Nutritional/herbal supplements have emerged as one of the major hepatotoxicity agents. DILI can manifest as predominantly hepatitis, bile duct injury or combination. Histological pattern recognition in the liver biopsy may help identify specific hepatotoxic agents causing DILI.

Spontaneous bacterial peritonitis (SBP) is a potentially life-threatening complication of ascites diagnosed by paracentesis. We determined predictors of SBP to facilitate patient selection. The 301 paracenteses performed in 119 patients (51 women, 68 men) from July to November 2015 were retrospectively reviewed. Presentation, lab data, depth of the deepest ascites pocket on ultrasound, total volume of ascites removed, absolute neutrophil count, and complications were studied. Of 301 paracenteses, 16 (5%) diagnosed SBP. On univariate analysis, SBP was associated negatively with history of cirrhosis and positively with history of cancer, abdominal pain, greater depth of the fluid pocket, prior SBP, and leukocytosis. Multivariate analysis using these variables to predict SBP was significant (P < 0.0001); only depth of the largest fluid pocket (P = 0.008) and complaint of abdominal pain (P = 0.006) were independent predictors. Receiver-operator curve analysis showed that a 5-cm cutoff of pocket depth yielded 100% sensitivity and 32% specificity. Two (0.1%) hemorrhagic complications occurred, one causing death and one necessitating laparotomy. In conclusion, deeper ascites pockets and abdominal pain are independent predictors of SBP. When the largest ascites pocket is <5 cm, the probability of SBP is nearly negligible. Given the potential for hemorrhagic complications, findings may help triage patients for paracentesis.